Antibody production: an endurance sport

Antibodies defend us against infections, so they often get described as weapons. And the cells that produce them could be weapon factories?. To understand recent research from immunologist Jerry Boss’s lab, a more appropriate metaphor is the distinction between sprinting and long-distance running.

Graduate student Madeline Price in Boss’s lab has been investigating how antibody-producing cells use glucose – the simple sugar– and how the cells’ patterns of gene activity reflect that usage. Cells can use glycolysis, which is inefficient but fast, analogous to sprinting, or oxidative phosphorylation, generating much more energy overall, more like long distance running.

As Boss and Price point out:

Immunology + Molecular Pathogenesis graduate student Madeline Price

Glycolytic metabolism produces 2 molecules of ATP per molecule of glucose, while oxidative phosphorylation produces 36 molecules of ATP from the same starting glucose molecule. Where oxidative phosphorylation generates more energy from ATP, glycolysis generates metabolic intermediates that are also useful for rapid cellular proliferation.

In their recent paper in Cell Reports, they lay out what happens to B cells, which can go on to become antibody secreting cells (ASCs), after an initial encounter with bacteria. The B cells first proliferate and upregulate both glycolysis and oxidative phosphorylation. However, upon differentiating, the cells shift their preference to oxidative phosphorylation. This is the opposite of the Warburg effect seen in tumor cells, which emphasize glycolysis. They even demonstrate that B cells have an increased propensity to differentiate under the influence of dichloroacetate, a (controversial) proposed anti-cancer drug. Price, Boss and colleagues also show that the shift in metabolism is under the control of a master regulator of differentiation called BLIMP1. They write:

ASCs skew this equilibrium toward oxidative phosphorylation and away from glycolysis, providing the most efficient use of glucose. Because ASCs each produce thousands of antibodies per second, it is likely that they require the maximal amount of energy to be derived from every molecule of glucose they consume.

Their conclusion:

Activation and terminal differentiation of B cells is a primary goal of many vaccinations. By providing a lucrative environment for B cells to use their metabolic flavor of choice, there is the potential to increase efficiency of B cell differentiation. This could increase vaccine responses and provide enhanced immunity.